JP5675820B2 - Implant devices with various bioactive agent loading configurations - Google Patents

Description

(Cross-reference of related applications)
This application is based on and claims the benefit of priority US Provisional Patent Application No. 61 / 244,36 filed on Sep. 22, 2009, the entire contents of which are hereby incorporated by reference. Incorporated into.

  Within the field of pharmaceutical formulations is the field of drug delivery formulations designed to release a bioactive agent over a desired time in a single administration. Depot formulation is one of the names used to describe such long acting formulations. Depot formulations can be manufactured in a number of ways. A typical formulation approach for preparing a depot formulation or implant is by the production of a solid matrix comprising a bioactive agent and a polymeric excipient. The purpose of using polymer excipients in the implant is to limit the inflow of water, which in turn controls the dissolution of the bioactive agent and the subsequent release of the bioactive agent from the implant matrix. In addition to the physical and chemical properties of the bioactive agent, the amount of bioactive agent in the implant contributes to the release rate of the bioactive agent. That is, increasing the amount of bioactive agent increases the release rate. Unfortunately, some implant formulations require large amounts of bioactive agent inside the implant in order to obtain sufficient bioactive agent to achieve the dose and duration requirements for a particular medical indication. However, incorporating a large amount of bioactive agent inside the implant may cause the bioactive agent to be released too quickly or even at an uncontrollable rate.

  Therefore, there is a need for new implant devices that can carry various amounts (including large amounts) of bioactive agents while still maintaining satisfactory release (especially sustained release profiles, release profiles with low initial bursts, etc.) It is said that. The present invention satisfies these and other needs.

  Described herein are implant devices that carry bioactive agents in various configurations, and the selection and use of them can customize the specific bioactive agent release profile from the implant device.

  The advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned through practice of the aspects described below. The advantages described below are realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It should be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only and are not restrictive.

(0006, 0007)
1 is an isometric cross-sectional view of an exemplary implant device having a core surrounded by a membrane shell. FIG. FIG. 2 is a top cross-sectional view of a coextrusion apparatus that can be used to form an implant device having a core surrounded by a membrane shell.

(0008)
Prior to disclosing and describing the compounds, compositions, composite materials, articles, devices and / or methods of the present invention, the embodiments described below are specific compounds, compositions, composite materials, articles, devices, methods or applications. It should be understood that this is not a limitation. Of course, these can vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

(0009)
In this specification and the claims that follow, a number of terms will be used, which shall be defined to have the following meanings:

(0010)
Throughout this specification, unless the context otherwise dictates, the term “comprise” or variations thereof (comprises, including, etc.) are described in any integer or step described Or it is understood to imply that an integer or group of steps is included but does not exclude other integers or steps or groups of integers or steps.

(0011)
It should be noted that the singular forms used in the specification and the appended claims include a plurality of objects unless the context clearly dictates otherwise. Thus, for example, reference to “a bioactive agent” includes a mixture of two or more such substances, and the like.

(0012)
“Optional” or “optionally” means that the event or situation described following these words may or may not occur, and the description includes this event or It means that a situation occurs and a case where it does not happen.

(0013)
Ranges may be expressed herein as from “about” one particular value and / or to “about” another particular value. When such a range is expressed, another aspect includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations with a prefix “about,” it will be understood that the particular value constitutes another aspect. It is further understood that the end points of each range are important both in relation to the other end point and independent of the other end point.

(0014)
% By weight of a component is based on the total mass of the formulation or composition in which the component is included, unless otherwise specified.

(0015)
A “releasable agent” is a material that can be mixed with a disclosed polymer and subsequently released from the polymer, for example, following erosion of the polymer.

(0016)
A “bioactive agent” is a substance that has biological activity. Biological agents can be used for treatment, diagnosis, healing, alleviation, prevention (ie prophylactic), remission, modulation. Alternatively, it may have another suitable effect on diseases, disorders, infectious diseases and the like. A “releasable bioactive agent” is one that can be released from the disclosed device. Bioactive agents also include substances that affect a patient's body structure or function, ie prodrugs, which become bioactive or more bioactive when placed in a predetermined physiological environment.

(0017)
Disclosed are compounds, compositions, and ingredients that can be used, can be used in, or are products of the disclosed methods and compositions. Although these and other materials are disclosed herein, combinations, subsets, interactions, groups, etc. of these materials are disclosed, and various individual and collective combinations and permutations of these compounds are disclosed. It is understood that each is specifically contemplated and described herein, even if not specifically disclosed. For example, if a number of different polymers and materials are disclosed and discussed, unless otherwise stated, individual and all combinations and permutations of polymers and materials are specifically contemplated. For this reason, for example, when an assembly consisting of molecules A, B, and C, an assembly consisting of molecules D, E, and F, and AD, which is an example of a combination molecule, are disclosed, Each is contemplated individually and collectively. Thus, in this example, each of the combinations AE, AF, BD, BE, BF, CD, CE, and CF is specifically contemplated. And should also be considered disclosed from the disclosure of A, B and C and D, E and F, and combinations AD. Similarly, any subset or combination of these is specifically contemplated and disclosed. Thus, for example, the sub-groups of AE, BF, and CE are specifically contemplated and disclosed from the disclosure of A, B, and C and D, E, and F and combination examples AD. Should be considered. This concept applies to all aspects of this disclosure including, but not limited to, steps in methods of making and using the disclosed compositions. Thus, if there are various additional steps that can be performed, each of these additional steps can be performed in any particular embodiment or combination of embodiments of the disclosed method, and each such combination can be It is understood that it is specifically intended and should be considered disclosed.

(0018)
In general, the implant device of the present invention includes a longitudinal body and proximal and distal ends (and proximal and distal end faces). The longitudinal body includes a biocompatible and / or biodegradable polymer. The longitudinal body includes a longitudinal core surface, the longitudinal core surface being (i) a partially or fully exposed surface, (ii) partially or completely coated with a bioactive agent, (Ii) partially or completely (ie, not exposed) polymer sheath (which may or may not contain a bioactive agent, and its surface may be coated with a bioactive agent or may contain a bioactive agent); Or a combination of (i), (ii) and (iii).

(0019)
The implant device is loaded with a bioactive agent according to a specific loading configuration depending on the desired release profile. By varying the bioactive agent carrying configuration in the implant device of the present invention, the release profile can be customized to specific needs and advanced release profiles can be achieved.

(0020)
In general, the bioactive agent can be present in the implant (ie, within the longitudinal body and / or the polymer sheath) or on any surface. Generally, the bioactive agent is (i) coated only on one or more of the proximal or distal end faces, (ii) one or more of the proximal or distal end faces and only part or all of the outer surface of the longitudinal body. (Iii) Coat part or all of the longitudinal body but not on either end face, (iv) Dissolve or disperse in the inner core (if present), (v) Longitudinal body (Vi) dissolved or dispersed in the polymer sheath (if present), (vii) absent in the polymer sheath (if present), or any combination of (i) to (viii) can do.

(0021)
In one embodiment, the implant device can be highly loaded. In this embodiment, the bioactive agent is dissolved or dispersed throughout the longitudinal body. The surface of the implant device can be coated with a bioactive agent, or the surface may not contain a bioactive agent. This aspect may include an example where the longitudinal body constitutes the inner core and is surrounded by a polymer sheath.

(0022)
In another aspect, the longitudinal body includes an inner core having a longitudinal core surface surrounded by a polymer sheath and has exposed proximal and distal end surfaces that are not surrounded by the polymer sheath. The polymer sheath includes a longitudinal outer surface that is substantially coextensive with the longitudinal core surface. The inner core includes a biodegradable polymer in which a bioactive agent is dissolved or dispersed. In one example, the polymer sheath does not contain a bioactive agent. In other examples, the polymer may contain a bioactive agent dissolved or dispersed. For example, referring to FIG. 1, an implant device 100 includes a longitudinal body 130 that includes an inner core 110 bearing a bioactive agent and a longitudinal core surface surrounded by and coextensive with a polymer sheath 150. The polymer sheath includes an outer polymer sheath surface 140. The implant device also includes a bioactive agent coating 120 on the proximal and / or distal end face, the proximal and / or distal end face having a portion of the end face formed by the outer polymer sheath (but the polymer sheath). And the portion of the end face formed by the inner core. In a similar embodiment, the bioactive agent can be coated on the longitudinal surface in addition to the coating on the end surface. In another embodiment, the bioactive agent may be coated on the longitudinal surface and not the proximal and distal surfaces. In yet another embodiment, the bioactive agent may be present within both the core and the polymer sheath (ie, dissolved or dispersed). In this embodiment, the drug concentration in the core and the surrounding polymer sheath can be the same or different.

(0023)
In another aspect, the longitudinal body includes an inner core having a longitudinal core surface surrounded by a polymer sheath and has exposed proximal and distal end surfaces that are not surrounded by the polymer sheath. The polymer sheath includes a longitudinal outer surface that is substantially coextensive with the longitudinal core surface. The inner core contains a biodegradable polymer and does not contain a bioactive agent. Alternatively, it has no dissolved or dispersed bioactive agent. In this embodiment, the bioactive agent can be coated on one or more of the outer surfaces, the outer surface including one or more of a longitudinal outer surface, a proximal end surface, a distal end surface, or a combination thereof, and the bioactivity Examples include coating the agent on some or all exposed surfaces of the implant device.

(0024)
In another aspect, the implant device includes a longitudinal body that may have a longitudinal surface that is exposed because it is surrounded or not surrounded by a polymeric membrane sheath. In this embodiment, the dissolved or dispersed longitudinal body and the bioactive agent are only present on one or more of the proximal or distal end faces.

(0025)
In one embodiment, an implant device having a core / sheath structure forms a core having a desired shape from a mixture of (a) a biodegradable polymer and any bioactive agent (if desired to be supported on the inner core). And (b) forming a membrane sheath surrounding the core, and (c) removing a portion of the membrane sheath surrounding the end surface to expose the proximal and distal end surfaces.

(0026)
In the case of a core / sheath configuration in which a bioactive agent is dissolved or dispersed in the inner core, the core of the implant device is formed by first mixing at least one biodegradable polymer with at least one bioactive agent. Can be achieved by generating. Mixing of the biodegradable polymer and the bioactive agent can be performed using techniques known in the art. For example, the polymer and bioactive agent can be dry blended using, for example, a Patterson Kelly V-Blender (ie, a blend of polymer and bioactive agent particulates) or processed prior to forming a core of the desired shape. It can be granulated before the step. It is contemplated that other ingredients (eg, excipients) may be mixed with the polymer and bioactive agent prior to processing the mixture into a core.

(0027)
A solvent may be used in the mixing step. However, in other embodiments, the mixing of the biodegradable polymer and the bioactive agent does not involve the use of a solvent. Numerous advantages can be realized by not using a solvent during mixing. First, the use of a solvent during mixing requires an additional processing step to remove this solvent. Second, if the delivery system is implanted in a patient, the solvent selected must be biocompatible if the residual solvent remains in the device. Solvents can adversely affect the overall morphology of the delivery system, which can lead to undesirable release patterns. The solvent can adversely affect the stability of the bioactive agent during the manufacturing process. Finally, the solvent level needs to be controlled because it must be low enough to meet regulatory guidelines.

(0028)
Processing of the mixture into the inner core can be performed under conditions such that the bioactive agent is intimately mixed and dispersed or dissolved throughout the polymer or only at specific sites in the polymer. The mixture can be processed into an inner core of the desired shape by various techniques, such as melt extrusion, injection molding, compression molding or roller compression into the desired shape or structure. Compression manufacturing techniques can include, but are not limited to, tableting. Depending on the processing conditions, the biodegradable polymer used as the starting material in the mixing step can be the same as or different from the polymer present in the final device. For example, the polymer being processed may undergo a polymerization or depolymerization reaction to eventually produce a polymer different from that used prior to processing. For this reason, as used herein, the term “polymer”, including both biocompatible and biodegradable polymers, refers to the polymer used as the starting material and the final polymer present in the final device. Cover.

(0029)
In one embodiment, an inner core having a desired shape is first processed (with or without bioactive agent) as discussed above, and then a membrane sheath surrounding the core is formed. In other aspects discussed below, the inner core and membrane sheath can be co-processed, eg, by coextrusion, to obtain an implant device. When the inner core is first formed, the membrane sheath can subsequently be formed using methods known in the art. In one embodiment, the membrane sheath can be formed by spray coating or dip coating a solution comprising a biocompatible polymer (and optionally a bioactive agent) on the inner core. In this embodiment, since the membrane sheath can be formed surrounding the entire inner core, the inner core does not have an exposed surface. After formation of the membrane sheath, a portion of the membrane sheath is removed, eg, by dissolving or physically cutting a portion of the membrane sheath, thereby removing the exposed inner core surface (ie, proximal or distal end surface). Can be obtained. In other embodiments, the membrane sheath can be formed surrounding only a portion of the core so that the core has an exposed surface after the membrane sheath is formed.

(0030)
In another embodiment, the core is formed by coextrusion of the implant device, eg, by extruding (a) a biodegradable polymer or alternatively a mixture of biodegradable polymer and bioactive agent from an inner coaxial nozzle. and, applying a film sheath having substantially coextensive surrounding the mixture was co-extruded at the same time from the outside coaxial nozzle, the core of the biocompatible polymer and the biologically active agent in (b) a biocompatible polymer or alternative To form a composite strand and can be prepared by a process comprising (c) cutting the composite strand of step (b) into one or more slats comprising a longitudinal surface and two end surfaces. For example, an implant device as shown in FIG. 1 can be prepared by this method.

(0031)
Referring to FIG. 2, the coextrusion process can be accomplished using a variety of coextrusion equipment known in the art. FIG. 2 shows a cross section 60 of such a device. In the coextrusion process, a polymer or mixture that can be produced as discussed above is flowed to the inner coaxial nozzle 65 and a biocompatible polymer or mixture that forms a membrane sheath is flowed to the outer coaxial nozzle 60. Next, the inner coaxial nozzle 65 and the outer coaxial nozzle 60 are reduced in width to form sections 68, 70, where a biocompatible polymer or mixture and a biodegradable polymer or biodegradable polymer / bioactive agent mixture. Are combined to form an implant device having a desired shape (in this example, a cylinder). The coextruded composite strand then exits the device from exit point 80. After coextrusion, the coextruded composite strand can be cut into one or more slats including a longitudinal surface and two end surfaces, as discussed above and shown in FIG. Thus, after cutting the coextruded strands, an implant device can be formed by cutting the strands into individual slats, each slat having a longitudinal surface and proximal and distal as discussed above. Including the end face. This strand can be cut to the desired number of slats to produce the desired number of implant devices or implant devices of the desired longitudinal length.

(0032)
Implant devices that are not core / sheath structures can be prepared using more simplified extrusion methods, such as single mold extrusion, and can be cut into one or more slats as discussed above. Can do.

(0033)
In some embodiments, the implant device includes a bioactive agent coating on one or more surfaces of the device. The bioactive agent coating may be applied to the implant device by preparing a suitable solution with the bioactive agent dispersed in a solvent and subsequently applying the solution to one or more exposed surfaces of the implant device. Can do. Application of the solution can be done by spraying, dipping, brushing the solution onto the desired surface of the implant device, followed by evaporation of the solvent if desired.

(0034)
Various biocompatible or biodegradable polymers can be used to form implant devices, including those used for membrane sheaths and / or those used as inner core polymers. The biocompatible polymer can also be a biodegradable polymer. In one embodiment, the biocompatible polymer is a polyester, polyhydroxyalkanoate, polyhydroxybutyrate, polydioxanone, polyhydroxyvalerate, polyanhydride, polyorthoester, polyphosphazene, polyphosphate, polyphosphoester, polydioxanone, Polyphosphoester, polyphosphate, polyphosphonate, polyphosphate, polyhydroxyalkanoate, polycarbonate, polyalkyl carbonate, polyorthocarbonate, polyesteramide, polyamide, polyamine, polypeptide, polyurethane, polyalkylene alkylate, polyalkylene oxalate, Polyalkylene succinate, polyhydroxy fatty acid, polyacetal, polycyanoacrylate, polyketal, Li ether esters, polyethers, polyalkylene glycols, polyalkylene oxides, polyethylene glycols, polyethylene oxide, polypeptide, may be one or more polysaccharides or polyvinyl pyrrolidone. Other non-biodegradable but durable biocompatible polymers include, without limitation, ethylene-vinyl acetate copolymers, polytetrafluoroethylene, polypropylene, polyethylene, and the like. Similarly, other suitable non-biodegradable polymers include, without limitation, silicones and polyurethanes.

(0035)
The biodegradable polymers that form the inner core or membrane sheath (if present) can include any of the biodegradable polymers listed above or other biodegradable polymers known in the art. In further embodiments, the biocompatible and / or biodegradable polymer is poly (lactide), poly (glycolide), poly (lactide-co-glycolide), poly (caprolactone), poly (orthoester), poly (phosphazene). ), Poly (hydroxybutyrate) or copolymers containing poly (hydroxybutarate), poly (lactide-co-caprolactone), polycarbonate, polyesteramide, polyanhydride, poly (dioxanone), poly (alkylene alkylate), Polyethylene glycol and polyorthoester copolymer, biodegradable polyurethane, poly (amino acid), polyamide, polyesteramide, polyetherester, polyacetal, polycyanoacrylate, poly (oxyethylene) / poly (oxypropylene) ) Copolymers, polyacetals, polyketals, polyphosphoesters, copolymers containing polyhydroxyvalerate or polyhydroxyvalerate, polyalkylene oxalate, polyalkylene succinate, poly (maleic acid), copolymers, terpolymers, combinations thereof Or it can be a blend.

(0036)
In yet another embodiment, useful biodegradable and biocompatible polymers are lactic acid, glycolic acid, lactide, glycolide, caprolactone, hydroxybutyrate, hydroxyvalerate, dioxanone, polyethylene glycol (PEG), polyethylene oxide or these It contains one or more residues of the combination. In yet another aspect, useful biodegradable polymers are those that include one or more residues of lactide, glycolide, caprolactone, or combinations thereof.

(0037)
In one embodiment, useful biodegradable and biocompatible polymers comprise one or more blocks of hydrophilic or water-soluble polymers, including but not limited to polyethylene glycol (PEG), polyvinyl pyrrolidone (PVP). , Lactide, glycolide, caprolactone or another biocompatible or biodegradable polymer containing combination thereof in combination with one or more blocks.

(0038)
In certain embodiments, the biodegradable and / or biocompatible polymer can include one or more lactide residues. For this purpose, the polymer may be any racemic and stereospecific form of lactide (including but not limited to L-lactide, D-lactide, D, L-lactide) or any combination thereof. Lactide residues may also be included. Useful polymers comprising lactide include poly (L-lactide), poly (D-lactide) and poly (DL-lactide) and poly (L-lactide-co-glycolide), poly (D-lactide-co-glycolide). ) And poly (DL-lactide-co-glycolide), including but not limited to poly (lactide-co-glycolide) or copolymers, terpolymers, combinations or blends thereof. Lactide / glycolide polymers can conveniently be produced by melt polymerization through ring opening of lactide and glycolide monomers. In addition, racemic DL-lactide, L-lactide and D-lactide polymers are commercially available. L-polymers are more crystalline and slower to resorb than DL-polymers. In addition to copolymers comprising glycolide and DL-lactide or L-lactide, copolymers of L-lactide and DL-lactide are commercially available. Lactide or glycolide homopolymers are also commercially available.

(0039)
If the biodegradable and / or biocompatible polymer is poly (lactide-co-glycolide), poly (lactide) or poly (glycolide), the amount of lactide and glycolide in the polymer can vary. In further embodiments, the biodegradable polymer comprises 0-100 mol%, 40-100 mol%, 50-100 mol%, 60-100 mol%, 70-100 mol% or 80-100 mol% lactide and 0 It contains ~ 100 mol%, 0-60 mol%, 10-40 mol%, 20-40 mol% or 30-40 mol% glycolide, the amount of lactide and glycolide being 100 mol%. In further embodiments, the biodegradable polymer is poly (lactide), 95: 5 poly (lactide-co-glycolide), 85:15 poly (lactide-co-glycolide), 75:25 poly (lactide-co-glycolide). 65:35 poly (lactide-co-glycolide) or 50:50 poly (lactide-co-glycolide), the ratio being a molar ratio.

(0040)
In further embodiments, the biodegradable and / or biocompatible polymer can be poly (caprolactone) or poly (lactide-co-caprolactone). In one embodiment, the polymer can be poly (lactide-caprolactone), and in various embodiments, 95: 5 poly (lactide-co-caprolactone), 85:15 poly (lactide-co-caprolactone), 75:25. It can be poly (lactide-co-caprolactone), 65:35 poly (lactide-co-caprolactone) or 50:50 poly (lactide-co-caprolactone), the ratio being molar ratio.

(0041)
Where the biodegradable or biocompatible polymer comprises a lactide polymer, the lactide polymer includes all racemic and stereospecific forms of lactide (although L-lactide, D-lactide, D, L-lactide Any lactide residue may be included including, but not limited to, or combinations thereof. Useful polymers comprising lactide include poly (L-lactide), poly (D-lactide) and poly (DL-lactide) and poly (L-lactide-co-glycolide), poly (D-lactide-co-glycolide). ) And poly (DL-lactide-co-glycolide), including but not limited to poly (lactide-co-glycolide) or copolymers, terpolymers, combinations or blends thereof. Lactide / glycolide polymers can be produced by ring opening of lactide and glycolide monomers. In addition, racemic DL-lactide, L-lactide and D-lactide polymers are commercially available. L-polymers are more crystalline and slower to resorb than DL-polymers. In addition to copolymers comprising glycolide and DL-lactide or L-lactide, copolymers of L-lactide and DL-lactide are commercially available. Lactide or glycolide homopolymers are also commercially available.

(0042)
In some embodiments, the disclosed biodegradable and / or biocompatible polymers are contacted with one or more plasticizers to alter the physical properties of the resulting composition (eg, reduce Tg). Or it may be desirable to mix. Usable plasticizers include all FDA approved plasticizers such as benzyl benzoate, cellulose acetate, cellulose acetate phthalate, chlorobutanol, dextrin, dibutyl sebacate, dimethyl sebacate, acetyl phthalate, diethyl phthalate dibutyl phthalate, di Propyl phthalate, dimethyl phthalate, dioctyl phthalate, methyl cellulose, ethyl cellulose, hydroxyl ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, gelatin, glycerin, glyceryl monostearate, monoglyceride, mono- and di-acetylated monoglyceride, glycerol, mannitol, mineral oil and Lanolin alcohol, petrolatum and lanolin alcohol, castor Oil, vegetable oil, coconut oil, polyethylene glycol, polymethacrylate and copolymers, polyvinylpyrrolidone, propylene carbonate, propylene glycol, sorbitol, suppository base, diacetin, triacetin, triethanolamine, ester of citric acid, triethyl citrate, citric acid Acetyl triethyl, acetyl tributyl citrate, triethyl citrate and esters of phosphoric acid are included.

(0043)
Bioerodible polymer erosion allows the release of substances in the inner core of the implant device. A variety of releasable materials can be used in the composition. In general, any material that is desired to release over time can be used. Thus, the releasable substance can be a bioactive agent, a cosmetic substance (such as a lotion) or another substance (such as an agricultural product). The releasable material can be dissolved or dispersed in the polymer and can be present in any suitable amount, which generally depends on the intended use of the composition.

(0044)
A wide variety of bioactive agents can be used with the implant device. The bioactive agent can be blended, mixed or otherwise combined with and / or coated on one or more surfaces of the inner core, membrane sheath biodegradable polymer, as discussed above. In one embodiment, the bioactive agent can be pre-formulated into defined particles (eg, by spray drying of sugar). In another embodiment, at least a portion of the bioactive agent can be dissolved in the biodegradable polymer. In further embodiments, at least a portion of the bioactive agent can be dispersed in the biodegradable polymer of the inner core and / or membrane sheath (if present).

(0045)
Mixing of the bioactive agent and the polymer can be done with or without an additional solvent (other than the polymer), as discussed above. The amount of bioactive agent incorporated into the composition will vary depending on the particular drug, the desired therapeutic effect and the desired time frame. Since various compositions are intended to provide a therapeutic regimen for various purposes, there is no critical lower or upper limit to the amount of drug incorporated into the composition. The lower limit generally depends on the activity of the drug and the time frame for its release from the device. One of ordinary skill in the pharmaceutical arts can determine the toxicity level and minimum effective amount of a given drug.

(0046)
Various forms of bioactive agents that can be released from the implant device into the patient's body can be used. Liquid or solid bioactive agents can be incorporated into the devices described herein. The bioactive agent can be water soluble or water insoluble. In some embodiments, the bioactive agent is at least slightly water soluble, preferably moderately water soluble. Bioactive agents can include salts of the active ingredients. Thus, the bioactive agent can be an acidic, basic or amphoteric salt. The bioactive agent can be a hydrogen-bondable nonionic molecule, a polar molecule or a molecular complex. Effective bioactivity or bioactivity is obtained by including the bioactive agent in the device, for example in the form of uncharged molecules, molecular complexes, salts, ethers, esters, amides, polymer / drug conjugates or other forms. be able to.

(0047)
Examples of bioactive agents that can be incorporated into the device include small molecules, peptides, proteins (eg hormones), enzymes, antibodies, antibody fragments, antibody conjugates, nucleic acids (eg aptamers, iRNA, siRNA, DNA, RNA, Antisense nucleic acids, etc., antisense nucleic acid analogs, etc.), VEGF inhibitors, macrocyclic lactones, dopamine agonists, dopamine antagonists, low molecular weight compounds, high molecular weight compounds or conjugated bioactive agents. . Bioactive agents contemplated for use in the disclosed compositions include anabolic agents, antacids, antiasthma drugs, anticholesterol and antilipid drugs, anticoagulants, anticonvulsants, antidiarrheals, antiemetics, Anti-infectives (including antibacterials and antimicrobials), anti-inflammatory agents, antiepileptics, antimetabolites, antiemetics, antineoplastic agents, antiobesity agents, antipyretics and analgesics, antispasmodics, antithrombotics , Antitussive, antiuricemia, antianginal, antihistamine, appetite suppressant, biologics, cerebral vasodilator, coronary dilator, bronchodilator, cytotoxic drug, decongestant, diuretic, Diagnostic agents, erythropoiesis agents, expectorants, gastrointestinal sedatives, hyperglycemic agents, hypnotics, hypoglycemic agents, immunomodulators, ion exchange resins, laxatives, mineral supplements, mucolytic agents, neuromuscular agents, peripheral blood vessels Dilators, psychotropic drugs, sedatives, stimulants, thyroid and antithyroid drugs, tissues殖剤, uterine relaxants, vitamins, or antigenic materials.

(0048)
Other bioactive agents include androgen inhibitors, polysaccharides, growth factors, hormones, anti-angiogenic factors, dextromethorphan, dextromethorphan hydrobromide, noscapine, carbetapentane citrate, clofedanol hydrochloride, malein Chlorpheniramine acid, phenindamine tartrate, pyrilamine maleate, doxylamine succinate, phenyltolamine citrate, phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, ephedrine, codeine phosphate, codeine morphine sulfate, mineral Supplements, cholestramine, N-acetylprocainamide, acetaminophen, aspirin, ibuprofen, phenylpropanol hydrochloride Emissions, caffeine, guaifenesin, aluminum hydroxide, magnesium hydroxide, peptides, polypeptides, proteins, amino acids, hormones (have overlapping), interferons, include cytokines and vaccines.

(0049)
Representative drugs that can be used as bioactive agents in the composition include peptide drugs, protein drugs, therapeutic antibodies, desensitizers, antigens, anti-infective agents such as antibiotics, antimicrobial agents Antiviral agents, antibacterial agents, antiparasitic agents, antifungal substances and combinations thereof, antiallergic agents, androgenic steroids, decongestants, hypnotics, steroidal anti-inflammatory agents, anticholinergics, sympathomimetics, Sedative, miosis, psychostimulant, tranquilizer, vaccine, estrogen, progesterone agonist, humoral agent, prostaglandin, analgesic, antispasmodic, antimalarial, antihistamine, cardioactive agent , Non-steroidal anti-inflammatory drugs, antiparkinsonian drugs, antihypertensive drugs, □ -adrenergic blockers, nutritional agents and benzophenanthridine Including, but not limited to, Lloyd. Bioactive agents can also be substances that can act as stimulants, sedatives, sleeping pills, analgesics, anticonvulsants and the like.

(0050)
Other bioactive agents include analgesics (eg, acetaminophen, acetylsalicylic acid, etc.); anesthetics (eg, lidocaine, xylocaine, etc.); (anorexic agents, eg, dexadrine, phendimetrazine tartrate, etc.); Drugs, such as methylprednisolone, ibuprofen, etc .; anti-asthma drugs (eg, terbutaline sulfate, theophylline, ephedrine, etc.); antibiotics (eg, sulfisoxazole, penicillin G, ampicillin, cephalosporin, amikacin, gentamicin, tetracycline, clocycline) Ramphenicol, erythromycin, clindamycin, isoniazid, rifampin, etc.); (antifungal agents such as amphotericin B, nystatin, ketoconazole, etc.); antiviral agents (eg acyclovir, amantadine, etc.); For example, cyclophosphamide, methotrexate, etretinate, etc.); anticoagulants (eg, heparin, warfarin, etc.); anticonvulsants (eg, phenytoin sodium, diazepam, etc.); antidepressants (eg, isocarboxazide, amoxapine, etc.); For example, diphenhydramine hydrochloride, chlorpheniramine maleate, etc.); hormones (eg, insulin, progestin, estrogen, corticoid, glucocorticoid, androgen, etc.); tranquilizers (eg, torazine, diazepam, chlorpromazine hydrochloride, reserpine, chlordiazepoxide hydrochloride, etc.); Drugs (eg belladonna alkaloids, dicyclomine hydrochloride, etc.); vitamins and minerals (eg essential amino acids, calcium, iron, potassium, zinc, vitamin B12, etc.); cardiovascular Kinetics (eg prazosin hydrochloride, nitroglycerin, propranolol hydrochloride, hydralazine hydrochloride, pancrelipase, succinate dehydrogenase etc.); peptides and proteins (eg LHRH, somatostatin, calcitonin, growth hormone, glucagon-like peptide, growth releasing factor) factor), angiotensin, FSH, EGF, bone morphogenetic factor (BMP), erythropoeitin (EPO), interferon, interleukin, collagen, fibrinogen, insulin, factor VIII, factor IX, Enbrel®, Rituxan (Registered trademark), Herceptin (registered trademark), α-glucosidase, Cerazyme / Ceredose (registered trademark), vasopressi ACTH, human serum albumin, γ-globulin, structural protein, blood product protein, complex protein, enzyme, antibody, monoclonal antibody, etc.); prostaglandin, nucleic acid, carbohydrate, fat, narcotic (eg, morphine, codeine, etc.); mental Examples include, but are not limited to, therapeutic agents, antimalarials, L-dopa, diuretics (eg, furosemide, spironolactone, etc.); and anti-ulcer agents (eg, lanthidine hydrochloride, cimetidine hydrochloride, etc.).

(0051)
Bioactive agents can also be immunomodulators, such as cytokines, interleukins, interferons, colony stimulating factors, tumor necrosis factors, etc., allergens such as cat dander, birch pollen, dust mites, grass pollen, etc .; bacteria (eg pneumonia) Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Streptococcus Pyrogenes (Corynebacterium diphteriae), Corynebacterium diphteriae , Clostridium tetani, Clostridium botu inum), Clostridium perfringens, Neisseria meningitides, Neisseria gonorrhoeae, Streptococcus mutans, Pseudomonas fungus, Pseudomonas Haemophilus parafluenzae, Bordetella pertussis, Francisella tularensis, Yersinia pestis, Vibrio cholerae (Vibrio cholerae) terium tuberculosis, mycobacterium leprae, syphilis treponema, Leptspirosis interrogans, lyme disease Borrelia burgddorferi, b. For example, smallpox, influenza A and B, RS virus (original: respiratory synctial. Respiratory syncytial?), Parainfluenza, measles, HIV, SARS, varicella-zoster, herpes simplex 1 and 2, cytomegalovirus (cytomeglavirus), Epstein・ Bar, rotavirus, rhinovirus, adenovirus, papilloma virus, poliovirus, mumps, rabies, rubella, rich Antigens of ucky virus, equine encephalitis, Japanese encephalitis, yellow fever, Rift Valley fever, lymphocytic choriomeningitis, hepatitis B, etc .; fungi, protozoa and parasites (eg Cryptococcuc neoformans), Histoplasma capsulatum, Candida albicans, Candida tropicalis, Nocardia asteroids, rick Rick tick rick tick Mycoplasma pneumoniae, Chlamyda psittaci, Trachoma chlamydia (Ch) amydia trachomatis), falciparum malaria parasite (Plasmodium falciparum), Trypanosoma brucei (Trypanasoma brucei), Entamoeba histolytica (Entamoeba histolytica), Toxoplasma gondii (Toxoplasma gondii), Trichomonas vaginalis (Trichomonas vaginalis), Schistosoma mansoni (Schistosoma mansoni) Etc.) antigens. These antigens can be in the form of inactivated whole organisms, peptides, proteins, glycoproteins, carbohydrates or combinations thereof.

(0052)
In a further specific embodiment, the bioactive agent comprises an antibiotic. Antibiotics include, for example, amikacin, gentamicin, kanamycin, neomycin, netilmycin, streptomycin, tobramycin, paromomycin, ansamycin, geldanamycin, herbimycin, carbacephem, loracarbef, carbapenem, ertapenem, dripenem, imipenem / silastatin, meropenem, cephalospome Phosphorus (first generation), cefadroxyl, cefazolin, cefalotin (cefalotin or cefalothin), cephalexin, cephalosporin (second generation), cefaclor, cephamandol, cefoxitin, cefprozil, cefuroxime, cephalosporin (third generation) Cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibutene, cef Tizoxime, ceftriaxone, cephalosporin (4th generation), cefepime, cephalosporin (5th generation), ceftbiprole, glycopeptide, teicoplanin, vancomycin, macrolide, azithromycin, clarithromycin, dirithromycin, Erythromycin, roxithromycin, troleandomycin, tethromycin, spectinomycin, monobactam, aztreonam, penicillin, amoxicillin, ampicillin, azulocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezcillin, methicillin, naficrine, naficrine , Piperacillin, ticarcillin, polypeptide, bacitracin, colistin, polymyxin B, quinolone, ciprofloxaci , Enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, trovafloxacin, sulfonamide, maphenide, prontodyl (initial), sulfacetamide, sulfamethizole, sulfanilimide (initial) ), Sulfasalazine, sulfisoxazole, trimethoprim, trimethoprim-sulfamethoxazole (cotrimoxazole) (TMP-SMX), tetracycline (including demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline, etc.), Arsphenamine, chloramphenicol, clindamycin, lincomycin, ethambutol, fosfomycin, fusidic acid, furazolidone, Isoniazid, linezolid, metronidazole, mupirocin, nitrofurantoin, platencimycin, pyrazinamide, quinupristin / dalfopristin, rifampicin (rifampin in the US), tinidazole, ropinerole, ivermectin, moxidectin, afamanotide (ofa) One or more of the following. In one embodiment, the bioactive agent can be a combination of rifampicin (rifampin in the United States) and minocycline.

(0053)
In some embodiments, the device itself may be a carrier and / or combined with other carriers or additives. Other pharmaceutical carriers can also be used. Examples of solid carriers other than polymers (when solid) include lactose, clay, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers other than polymers (when liquid) are liquid sugar, peanut oil, olive oil and water. Examples of gaseous carriers include carbon dioxide and nitrogen. Other pharmaceutically acceptable carriers or ingredients that can be mixed with the bioactive agent can include, for example, fatty acids, sugars, salts.

(0054)
In one embodiment, the composition can be present in a kit. The kit can include a package or container suitable for the composition. Examples include, without limitation, sterilization packages. Since the disclosed composition is suitable for use as an injectable composition, a pre-packaged injection device can be enclosed in the kit, and the pre-packaged injection device includes an injection device loaded with an implant device. Including. Suitable injection devices include, without limitation, syringes, trocars and the like.

(0055)
As discussed above, the implant device can be used to administer a bioactive agent to a patient in need thereof, eg, to treat a disease for which the bioactive agent is effective. The composition can be administered to any tissue or bodily fluid of the patient. Similarly, the administration method can be any suitable method, for example, subcutaneous injection, oral administration, parenteral administration, parental administration, internal administration, and the like. In some embodiments, a liquid composition comprising one or more low viscosity polymers can be injected into a patient. The nature of the composition to be administered will generally be selected based on the desired dose of bioactive agent and will vary greatly depending on the disease, but can be readily determined by one skilled in the pharmaceutical arts.

(0056)
An “effective amount” of a composition is the amount of the composition that can achieve the desired therapeutic outcome. Thus, the effective amount will vary widely depending on the composition, bioactive agent and the disease or condition being treated. The actual effective amount of the dose of the composition administered to the patient is the physical and physiological factors (weight, severity of the condition, type of disease being treated, previous or concurrent therapeutic intervention, The patient's idiopathic disease, etc.) and can depend on the route of administration. Depending on the dose and route of administration, the preferred number of doses and / or effective dose may vary according to patient response. One skilled in the art can determine an effective amount of the disclosed pharmaceutical composition.

(0057)
In some non-limiting examples, the dose is about 1 μg / kg / body weight, about 5 μg / kg / body weight, about 10 μg / kg / body weight, about 50 μg / kg / body weight, about 100 μg / kg per administration. / Body weight, about 200 μg / kg / body weight, about 350 μg / kg / body weight, about 500 μg / kg / body weight, about 1 mg / kg / body weight, about 5 mg / kg / body weight, about 10 mg / kg / body weight, about 50 mg / kg / Body weight, about 100 mg / kg / body weight, about 200 mg / kg / body weight, about 350 mg / kg / body weight, about 500 mg / kg / body weight, about 1000 mg / kg / body weight or more and can be derived in these ranges Any range may be included. In a non-limiting example of a range derivable from the numerical values listed herein, based on the above numerical values, from about 5 mg / kg / body weight to about 100 mg / kg / body weight, from about 5 μg / kg / body weight to about 500 mg / Kg / body weight can be administered.

(0058)
The bioactive agent may be present in the implant device at any suitable weight percent, such as a significantly higher weight percent loading, eg, up to 40% loading of the implant device or device weight. In one embodiment, an implant device can be used to alter the pharmacokinetics of a bioactive agent.

(0059)
The composition comprising the implant device can be administered to any desired patient. The patient can be a vertebrate, such as a mammal, fish, bird, reptile or amphibian. A patient of the methods disclosed herein can be, for example, a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term patient does not denote a particular age or gender. For this reason, it is intended to cover adult and neonatal (pup) patients and fetuses regardless of sex. In addition, the composition can be administered by any suitable route, including parenteral and oral routes, among others. In one preferred embodiment, the composition can be injected into a patient.

(0060)
Various modifications and changes can be made to the compounds, composites, kits, articles, devices, compositions and methods described herein. Other aspects of the compounds, composite materials, kits, articles, devices, compositions and methods described herein are the specifications of the compounds, composite materials, kits, articles, devices, compositions and methods disclosed herein. And it is clear when considering the practice. The specifications and examples are intended to be considered exemplary.

Claims (10)

An implant device,
A longitudinal body having an inner core including a longitudinal surface surrounded by a polymer sheath and exposed proximal and distal end surfaces not surrounded by the polymer sheath;
The polymer sheath includes a longitudinal outer surface having substantially the same extent as the longitudinal inner core surface;
At least one of the inner core or the polymer over sheet over scan, but includes a biodegradable polymer,
Both the inner core and the polymer sheath comprise a dissolved or dispersed bioactive agent;
The inner core and the polymer sheath comprise different concentrations of bioactive agent, wherein the concentration of bioactive agent in the polymer sheath is higher than the concentration of bioactive agent in the inner core; and
The implant device, wherein the bioactive agent of the inner core and the polymer sheath contains up to 40% by weight, based on the weight of the implant device. The proximal end face, one or more of the distal end face or longitudinal outer surfaces are coated with a biocompatible or biodegradable coating polymer implant device of claim 1. The proximal end face, one or more of the distal end face or longitudinal outer surfaces are coated with the same or a different bioactive agent dissolved or dispersed bioactive agent to the inner core and / or the polymer sheath, to claim 1 The implant device as described. The implant device of claim 1 , wherein the polymer sheath comprises a polymer that forms a membrane sheath around the inner core. The implant of claim 1 , wherein the longitudinal body of the inner core comprises poly (lactide), poly (glycolide), poly (caprolactone), poly (lactide-co-glycolide) or mixtures, combinations or copolymers thereof. device. The implant of claim 1, wherein the longitudinal body of the polymer sheath comprises poly (lactide), poly (glycolide), poly (caprolactone), poly (lactide-co-glycolide) or mixtures, combinations or copolymers thereof. device. The implant device of claim 1, wherein both the inner core and the polymer sheath comprise a biodegradable polymer. The longitudinal body of both the inner core and the polymer sheath comprises poly (lactide), poly (glycolide), poly (caprolactone), poly (lactide-co-glycolide) or mixtures, combinations or copolymers thereof. Item 8. The implant device according to Item 7. The implant device of claim 1, wherein the bioactive agent dissolved or dispersed within the inner body and the longitudinal body of the polymer sheath is a small molecule. The implant device of claim 1, wherein the implant device is configured to be loaded into an injection device.

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